Final Report Summary - NMRPAMS (NMDA receptor processing in an animal model for schizophrenia)
The pathophysiological mechanisms causing schizophrenia are not well known. In patients, schizophrenia is characterised by several devastating symptoms including hallucinations, emotional isolation and serious cognitive deficits. Altered neurotransmission through the glutamate neurotransmitter system has been linked to this devastating psychiatric illness.
In particular, observations that functional antagonism of the N-methyl-D-apartate (NMDA) glutamate receptor by phencyclidine (PCP) worsens all symptom groups in patients and induces a schizophrenia-like psychosis in healthy volunteers have implicated this receptor system in schizophrenia. The NMDA receptor, which is principally expressed in postsynaptic neurons, is amultimeric protein assembly consisting of the obligatory NR1 subunit in different constellations with NR2A or NR2B subunits.
Through alternative splicing of the NR1 subunit, several regulatory domains are introduced in the receptor, which significantly influence early processing of the receptor including its assembly and forward trafficking. In a similar way, receptors assembled from NR2A and NR2B proteins contribute with functional specialisation of the receptor.
Studies in postmortem brain indicate that mechanisms associated with early NMDA receptor processing might be altered in schizophrenia. This includes evidence for altered NR1 splicing and compromised trafficking of NR2B-type NMDA receptors in cortical dendrites.
In particular, observations that functional antagonism of the N-methyl-D-apartate (NMDA) glutamate receptor by phencyclidine (PCP) worsens all symptom groups in patients and induces a schizophrenia-like psychosis in healthy volunteers have implicated this receptor system in schizophrenia. The NMDA receptor, which is principally expressed in postsynaptic neurons, is amultimeric protein assembly consisting of the obligatory NR1 subunit in different constellations with NR2A or NR2B subunits.
Through alternative splicing of the NR1 subunit, several regulatory domains are introduced in the receptor, which significantly influence early processing of the receptor including its assembly and forward trafficking. In a similar way, receptors assembled from NR2A and NR2B proteins contribute with functional specialisation of the receptor.
Studies in postmortem brain indicate that mechanisms associated with early NMDA receptor processing might be altered in schizophrenia. This includes evidence for altered NR1 splicing and compromised trafficking of NR2B-type NMDA receptors in cortical dendrites.
